Inorganic phosphorous is essential for multiple biological functions such as intracellular signal transduction, production and function of cell membranes and energy exchange. Although more than 80% of total body phosphorous is stored in bones and teeth phosphorous is also found in the serum, primarily as phosphate anions such as H2PO4− and H2PO42−.
Normal kidneys filter large amounts of organic phosphate of which more than 90% is reabsorbed by the renal tubules. Early renal dysfunction reduces filtered phosphate but also decreases tubular reabsorption, so that the urinary phosphate excretion continues to match gastrointestinal (GI) absorption. Consequently, the net balance between phosphate input and output is maintained for a period of time with only little change in serum phosphate levels. However, in patients with chronic kidney disease (CKD) Stage IV or stage V (also known as end stage renal disease ESRD), this homeostatic mechanism fails resulting in positive phosphate balance and progressive hyperphosphatemia. Hyperphosphatemia is a condition where the serum phosphate levels are greater than 5 mg/dL in adults or 7 mg/dL in children or adolescents.
Secondary hyperparathyroidism, renal osteodystrophy and soft tissue calcification are important consequences of hyperphosphatemia. Inadequate control of serum phosphorus contributes to elevated calcium-phosphorus product (Ca×P) which can lead to calcification of the cardiovascular system, including the myocardium, cardiac valves, and coronary arteries. This calcification is the major cause of death in end-stage renal disease (ESRD)
Consequently, phosphate control remains an important therapeutic target in management of CKD, not only to halt progression to secondary hyperparathyroidism but also to reduce the risk of vascular calcification and cardiovascular mortality. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate; removal of phosphate with dialysis and inhibition of intestinal phosphate absorption with phosphate binders.
A typical diet includes 1000-1200 mg of dietary phosphate per day from foods such as diary products, meats whole grains of which 800 mg is ultimately absorbed. Dietary phosphate reduction can help control serum phosphate levels but because most dietary phosphate is derived from protein, it is difficult to achieve phosphate control without significant reductions in protein intake. Low-phosphate diets are unpalatable and the risk of protein malnutrition outweighs any benefit of controlling serum phosphate levels.
Kinetic studies of hemodialysis have shown that since phosphate is predominantly intracellular, serum levels drop rapidly in the first 1-2 hours of dialysis and then reach a plateau. They then rise relatively quickly in the first few hours after termination of dialysis, the so-called ‘rebound phenomenon.’ The administration of dietary phosphate binders is therefore necessary in most patients on dialysis to effectively manage their hyperphosphatemia.
Phosphate binders are more effective at binding dietary phosphate than endogenous phosphate. Therefore, phosphate binders are currently administered with meals, to bind dietary phosphate before it is absorbed by the body and thus optimize the phosphate binding efficiency.
Use of aluminum-based phosphate binders was largely abandoned because of concerns over accumulation and major toxicities including dialysis encephalopathy, cognitive disturbances and osteomalacia. Calcium-based agents replaced aluminum but their prolonged administration can result in hypercalcemia. In addition they can result in over-suppression of parathyroid hormone (PTH), and can cause both soft tissue and vascular calcification. Magnesium-containing phosphate binders can be used as an alternative to calcium-based agents but generally they are less effective, and are associated with increased serum magnesium levels and diarrhea. Sevelamer hydrochloride was the first synthetic non-aluminium and calcium-free phosphate binder to become available. Metabolic acidosis, and cost are limiting factors affecting the wider use of sevelamer hydrochloride.
The need for effective treatments with better safety profiles led to the introduction lanthanum carbonate. Lanthanum carbonate is a known phosphate binder and is used to reduce phosphate levels in patients with hyperphosphatemia specifically those patients with hyperphosphatemia caused by end stage renal disease. Lanthanum carbonate is currently available from Shire US Inc. in 500, 750, and 1000 mg chewable tablets, marketed under the trade name, Fosrenol®.
U.S. Pat. No. 5,968,976 describes the use of La2 (CO3)3.xH2O, where x has a value of 3 to 6, for the preparation of a medicament for the treatment of hyperphosphataemia by administration into the gastrointestinal tract. The patent discloses dosage forms for oral administration like solid forms such as tablets, capsules and suspensions or syrups. Though this patent discloses word “suspension” as a dosage form, suspensions have not been exemplified or taught anywhere in the specification
United States Patent Application 2008/0125394 relates to a continuous slow release oral pharmaceutical compositions of substances capable of binding phosphorus, which when administered during fasting periods provides an improved treatment of hyperphosphatemia by binding the phosphorous secreted in the saliva and other gastric secretions. This patent explicitly describes about determination of phosphorus in saliva, binding the phosphorus that are secreted in saliva. And thus the compositions need to be retained in mouth for long period of time; the formulations include chewing gums, chewable tablets, powders, etc.
PCT application WO2004/016553 relates to rare earth metal compounds of porous nature. The patent application further relates to the method of making the rare earth metal compounds and methods of using said rare earth metal compounds. The patent application specifically relates to the lanthanum oxychloride, anhydrous lanthanum oxycarbonate, and hydrated lanthanum oxycarbonate having porous structure and improved phosphate binding capacity.
Despite the merits of the above mentioned compositions, the management of hyperphosphatemia in patients with chronic kidney disease remains challenging.
Chewable tablets are the only dosage form available for patients currently. The current dosage form carries many drawbacks for the treatment of hyperphosphatemia. Although chronic kidney disease (CKD) is found in persons of all ages, the highest incidence rate of end stage renal disease (ESRD) occurs in patients older than 65 years. As per the National Health and Nutrition Examination Survey (NHANES) III data, the prevalence of chronic kidney disease was 37.8% among patients older than 70 years. Patients older than 60 years of age have difficulties in chewing. The surface area of the lanthanum carbonate depends upon the thoroughness of the patient's chewing, resulting in a wide variance of effectiveness of phosphate binding.
Additionally for patients who have dentures, who are intubated and who are receiving enteral tube feedings who are unable to chew; medications are commonly crushed and administered through the nasogastric tube. Since lanthanum powder is un-dissolvable in liquids these tablets when crushed, remain as large granules, even after a period of many hours. This significantly reduces phosphate binding efficacy.
Furthermore, Fosrenol® chewable tablets are of substantial size, ranging in diameter from 18 mm for the 500 mg strength and 22 mm for the 1000 mg strength. The US Food and Drug Administration (FDA) has recently added lanthanum carbonate to the list of drugs to be monitored based on potential signs of serious risks specifically to monitor any swallowing complications, gastrointestinal obstruction (attributed to tablet hardness).
Also, Phosphate binders like lanthanum carbonate are only one of the many medications that patients with stage 5 chronic kidney disease are prescribed. A recent survey, suggests that patients undergoing dialysis treatment were prescribed an average of 12 different medications. The cumulative effect of multiple dosing regimens can impose a confusing and possibly overwhelming burden on a patient. In addition this high daily tablet burden associated with phosphate binders may contribute to poor patient adherence.
Furthermore patients suffering from End Stage Renal Disease (ESRD), severely injured patients, elderly or senile patients, mentally handicapped patients or other patients may require special administration of the Lanthanum carbonate. Liquid formulations, for example solutions, suspensions, dispersion etc, provide ease of administration and increase compliance among certain patient populations by enhancing taste and/or texture of the drug being administered.
At the moment, Lanthanum salts/compounds are not available as a liquid formulation at all but only as a solid tablet. As elucidated above the considerable size of chewable tablets coupled with poor patient compliance leads to inadequate therapeutic delivery. Thus there exists an unmet need in the current armamentarium of physician to treat chronic kidney disease.